P1298: THE IRAK-4 INHIBITOR EMAVUSERTIB (CA-4948) FOR THE TREATMENT OF PRIMARY CNS LYMPHOMA
Authors: C. Von Roemeling, M. Iqbal, B. Doonan, L. Hoang-Minh, K. Klippel, H. Tun, D. Mitchell
Journal: HemaSphere (2022)

Background: Primary central nervous system lymphoma (PCNSL) is an aggressive brain tumor accounting for 3% of all CNS malignancies and is usually associated with poor prognosis. 5-year survival is less than 30% with current treatment options. Standard of care treatment includes induction with high-dose methotrexate based chemoimmunotherapy followed by consolidation with autologous stem cell transplant or whole brain radiation. However, more than half of PCNSL patients are not eligible for this type of intensive therapeutic intervention. Novel treatment strategies with better efficacy and toxicity profile are urgently needed. Toll-like receptor signaling pathway via MyD88/IRAK-4 signalosome is constitutively active in PCNSL secondary to MYD88 L265P mutation and represents an excellent therapeutic target. Emavusertib (CA-4948) is an oral first-in-class small molecule inhibitor of IRAK4 that has demonstrated clinical activity in patients with systemic Non-Hodgkin's Lymphoma, however it has not been evaluated in the CNS space. Aims: In this study we examine translational and clinical therapeutic applicability and efficacy of emavusertib for the treatment of PCNSL. Methods: Using multiparameter immunohistochemistry (IHC) and proteomics analysis, IRAK-1, IRAK-4, and NF-κB pathway activation were examined in patient PCNSL tissues as compared to normal controls. Plasma, cerebrospinal fluid, and brain tissue were assessed via UPLC-MS/MS for emavusertib drug concentration following single oral high dose in a murine model. Using an aggressive preclinical A20 immunocompetent CNSL model, preclinical therapeutic activity of emavusertib was evaluated with assessment of downstream biomarker response to treatment including phospho-NF-κB, phospho-ERK1/2, and phospho-P38 in control and treated animals by multi-parameter IHC. We also report therapeutic response in a relapsed/refractory PCNSL patient enrolled in a Phase I/II clinical trial (TakeAim) assessing the combination of emavusertib and Ibrutinib. Results: Our data confirm elevated IRAK-1, IRAK-4, and NF-κB signaling in patient PCNSL. We also demonstrate that emavusertib can achieve therapeutically relevant concentrations in the brain parenchyma and shows single-agent activity in an aggressive preclinical model of PCNSL. We further confirm decreased ERK1/2, MAPK and NF-κB activation in response to preclinical emavusertib treatment, indicative of downstream effect of IRAK-4 inhibition. Finally, one patient who could not tolerate standard therapies and was resistant to Ibrutinib achieved complete response when treated with the combination of emavusertib and Ibrutinib, providing early clinical evidence of CNS penetration and anti-tumor activity of emavusertib. Summary/Conclusion: Herein we confirm for the first time that targeted inhibition of IRAK-4 with the oral small molecule inhibitor emavusertib demonstrates preclinical and clinical therapeutic activity against CNS lymphoma. Further evaluation of this agent for the treatment of PCNSL is warranted.